Zika virus (ZIKV) is an insect borne flavivirus which until recently was found within a narrow equatorial belt from Africa to Asia. ZIKV has emerged across the globe and has reached pandemic levels, spreading to Mexico, Central America, the Caribbean and South America. While ZIKV usually causes mild disease, infection of pregnant women has been suspected to cause a significant increase in babies born with microcephaly in Brazil, starting in late 2015, presumed to have become infected transplacentally a previously unknown route of infection. The association of ZIKV with abnormal brain development in the fetus has been supported by the recent detection of ZIKV RNA sequences and antigens along with neurodegeneration in aborted fetuses and babies that died soon after birth. Thus it is vital that we learn as much as possible of how ZIKV replicates and interacts with its host, including in cells of the CNS. The type I IFN response is an early potent antiviral response to viral invasion that can have a major impact on restricting virus spread as evidenced by significantly increased virus replication and rapid mortality as well as loss of organ tropism barriers observed in mice lacking type I IFN signaling. The CNS expresses low levels of interferon signaling genes compared to peripheral organs suggesting the CNS may be less prepared to restrict viral invasion. In addition, viruses suppress or evade the host immune response in order to facilitate their replication within a host and cause disease and therefore encode proteins with host IFN antagonist activities. The outcome of infection therefore depends on the balance of host immune defenses and virus encoded virulence factors and this can differ among viruses and tissue types. We have carried out extensive studies of IFN signaling responses to neurovirulent murine coronavirus in various cell types in vitro as well as in the CNS and the periphery of mice. We propose to use our expertise as well as information gathered, along with our recent data demonstrating robust replication of ZIKV in human A549 cells where it activates the OAS-RNase L pathway and in primary murine neuronal and glial cell cultures to test the hypothesis that cell type and tissue specific differences in the type I IFN response to ZIKV may contribute to susceptibility of the fetal brain to ZIKV-induced pathology. In Aim 1 we will investigate the IFN signaling pathways during ZIKV infected human A549 cells and CRIPSR/Cas9 engineered knockout A549 cells as well as primary murine neuronal and glial cell cultures. In Aim 2 we will investigate ZIKV replication and IFN response in vivo in embryonic and neonatal mice. Upon completion of these aims we will have gained an understanding of the type I IFN response to ZIKV in vitro in human cells as well as murine CNS cells. We will also know more about IFN signaling in the developing mouse embryo and spread of ZIKV from infected mothers. These two approaches combined will aid in understanding the impact of IFN signaling on ZIKV infection and spread and in the more long term identify targets for the development of therapeutic strategies to treat ZIKV-induced disease.